Traditional approaches to cancer drug development have failed to identify anticancer drugs that have a significant therapeutic benefit for most cancer patients. New approaches to cancer drug development are clearly needed. Recent information suggests that cancer can be considered a disease of deranged intracellular signalling. We will use cancer cell- specific intracellular signalling targets and screen diverse natural product extracts as sources of novel chemical structures to provide specific inhibitors of the targets as potential drugs for the prevention and treatment of cancer. In this project we will focus our work on phospholipid metabolism that occurs as a major early event in signalling by a number of oncogenes important to human cancer. The enzymes of phospholipid metabolism, thus, offer attractive surrogate targets for the inhibition of oncogene signalling. The targets we will study initially are: phosphatidylinositol specific phospholipase C, phosphatidylinositol- 3-kinase and phospholipase D. We will conduct mechanistic studies of these signalling targets using molecular and cellular biology techniques to further define their roles in cell growth and transformation. We will screen natural product extracts from Chinese traditional and other medicinal plants, bacterial and fungal fermentation products and natural product-based combinatorial libraries, to identify novel inhibitors of these signalling targets. We will use the inhibitors we identify to modulate the activity of these targets in experimental systems and relate inhibition of the target to inhibition of cell growth and in vivo antitumor activity. The goal of our studies is to identify and develop novel natural product inhibitors of oncogene signalling pathways for the effective prevention and treatment of cancer.